Patent GB-1433141-A (GB)
Title: Antibiotics
IPC: C07D501/00
Filed: 1972-07-07
Abstract: 1433141 Antibiotics GLAXO LABORATORIES Ltd 14 June 1973 [7 July 1972] 32004/72 Heading C2C The invention is directed to compounds which are selected from the group consisting of (a) 7#-acylamido -3-acetoxymethylceph-3- em-4-carboxylic acids (syn-isomers) in which the 7#-acylamido group is 2-hydroxyimino-2- (thien - 3 - yl)acetamido; 2 - hydroxyimino- 2- furylacetamido; 2 - ethoxycarbonyloxyimino - 2 - (thien - 2 - yl)acetamido; 2- acetoxyimino - 2(thien - 2 - yl)acetamido; 2 - (2- chloroethylcarbamoyloxyimino - 2 - (thien - 2- yl)acetamido; or 2 - hydroxyimino - 2 - (pyrid- 4 - yl)acetamido, (b) 3 - (substituted methyl)- 7# - [2 - hydroxyimino - 2 - (thien - 2 - yl)- acetamido ceph - 3 - em - 4 - carboxylic acids (syn-isomers) in which the group at the 3- position is acetylthiomethyl, crotonyloxymethyl, 1 - phenyltetrazol - 5 - ylthiomethyl, 1 - methyl tetrazol - 5 - ylthiomethyl, or 5- phenyl - 1,3,4 - oxa - diazol - 2 - ylthiomethyl, (c) 3 - (substituted methyl) - 7# - [2 - hydroxyimino - 2(furyl) - acetamido]ceph - 3 - em - 4- carboxylic acid (syn-isomers) in which the group at the 3-position is 4-carbamoylpyridinium-methyl, 1-methyl tetrazol-5-ylthiomethyl or 5 - methyl - 1,3,4 - thia - diazol - 2 - ylthiomethyl and (d) 6#-acylamido-2,2-dimethylpenam - 3α - carboxylic acids (syn - isomers) in which the 6#-acylamido group is 2-hydroxyimino - 2 - (thienyl) acetamido, or 2 - hydroxyimino - 2 - (furyl) acetamido and non - toxic salts and esters thereof. The above compounds have the Formula I wherein R<SP>α</SP> and X have appropriate meanings corresponding to those embraced by (a)-(d) above, and may be prepared by either (A) condensing a compound of formula wherein B is > S or > S # O, X has the abovedefined meaning, R<SP>1</SP> is H or a carboxyl blocking group, and the dotted line indicates that the compound may be a ceph-2-em or ceph-3-em compound or an acid addition salt thereof with an acylating agent which is the syn-isomer corresponding to the acid R<SP>α</SP>.OH wherein R<SP>α</SP> has the above-defined meanings, or with an acylating agent corresponding to an acid which is a precursor for the acid R<SP>α</SP>.OH or (B) reacting a compound of formula  or of formula with R<SP>α</SP>, OH or a percursor therefor (which acid does not contain a free hydroxy imino group; or (C) reacting a compound of formula wherein Acyl is R<SP>α</SP> or a precursor thereof and X<SP>1</SP> is a replaceable residue of a nucleophile, with a nucleophile whereafter in each instance, any of the following (D) are carried out: (i) conversion of a precursor for the desired R<SP>α</SP> group into that said group, (ii) conversion of a #<SP>2</SP> isomer into a #<SP>3</SP> isomer, (iii) removal of any carboxyl blocking groups, (iv) reduction of a compound in which B is > S # O to form the compound in which B is > S and (E) recovering the desired compound of Formula (I) or a non-toxic salt or ester thereof, if necessary, after separation of isomer. The acylation may be carried out at -50‹ to +50‹ C., in the presence of an acidbinding agent (e.g. a tertiary amine, inorganic base or oxirane) and a condensation agent (e.g. a carbodiimide, a carbonyl compound or an isoxazolinium salt). Acylation may be effected with an acid halide or an amide-forming derivative of the acid. The Specification also describes the following compounds and their preparation (1) ethyl thien-3-ylglyoxylate which is prepared by adding 3-bromothiophene to nbutyl lithium in ether and reacting the resulting slurry with diethyl oxalate in ether, (2) thien- 3-ylgloxylic acid which is prepared by reacting methanol with a mixture of sodium hydroxide and ethyl thien-3-yl glyoxylate, (3) 2-hydroxyimino-2-(thien-3-yl)-acetic acid, prepared by adding to hydroxylamine hydrochloride in methanol a methanolic solution of sodium methoxide, and adding thien-3-yl-gloxylic acid to the resulting mixture, (4) 2-dichloroacetoxyimino - 2 - (thienyl - 3 - yl) acetyl chloride (syn-isomer), prepared by mixing 2-hydroxyimino-2-(thien-3-yl) acetic acid with dichloroacetyl chloride in dry methylene chloride and then mixing with phosphorous pentachloride in dry methylene chloride, (5) 2-hydroxyimino- 2-(fur-2-yl) acetic acids, prepared by mixing methanolic solutions of hydroxylamine, sodium methoxide and fur-2-yl glyoxylic acid, (6) 2- diohloroacetoxyimino - 2 - (fur - 2 - yl)acetyl chloride (syn-isomer) prepared by mixing dichloroacetyl chloride and 2-hydroxyimino-2- (fur-2-yl) acetic acid and then mixing with phosphorous pentachloride, (7) 2-dichloroacetoxyimino -2 - (thien - 2 - yl) acetyl chloride (syn-isomer) prepared from the corresponding acid in the manner indicated in (4) above, (8) diphenyl - 3 - acetylthiomethyl - 7# - formamidoceph - 3 - em - 4 - carboxylate - 1# - oxide prepared by reacting diphenyl 3-bromomethyl- 7 - # - formamidoceph - 3 - em - 4 - carboxylate- 1 #-oxide with ethane thiolic acid, (9) diphenylmethyl 3 -acetylthiomethyl-7#-formamidoceph- 3-em-4-carboxylate, prepared by reacting compound (8) with potassium iodide, acetylchloride and sodium metabisulphite, (10) diphenylmethyl - 3 - (1 - methyltetrazol - 5 - ylthiomethyl) - 7# - (2 - thienylacetamido - ceph - 3 - em- 4-carboxylate prepared by mixing diphenylmethyl 3 - bromomethyl - 7# - (2 - thienylacetamido) - ceph - 3 - em - 4 - carboxylate, 5 - mercapto - 1 - methyltetrazole and triethylamine, (11) diphenylmethyl - 7# - amino- 3 - (1 - methyltetrazol - 5 - yl - thiomethyl)- ceph - 3 - em - 4 - carboxylate prepared by reacting compound (10) with phosphorous pentachloride, and (12) diphenylmethyl-7#- amino - 3(5 - phenyl, - 1,3,4 - oxadiazol - 2- ylthiomethyl) - ceph - 3 - em - 4 - carboxylate hydrochloride prepared by mixing diphenylmethyl - 3 - bromomethyl - 7# - formamidoceph- 3 - em - 4 - carboxylate - 1# - oxide with triethyl amine and 5-mercapto-2-phenyl-1,3,4- oxadiazole, followed by treatment with phosphorous tribromide and sodium bicarbonate in methylene dichloride to give the carboxylate which is then treated with phosphorous oxychloride to give compound (12) Pharmaceutical compositions comprising the above novel compounds and a carrier therefor are described in usual forms and having antibiotic activity.